Sepsis is a leading cause of death in critical care units. Our long-term goal is to understand the mechanisms of sepsis-induced multi-organ failure and to identify potential new therapeutic opportunities for this deadly disease. Current evidence suggests that mitochondrial reactive oxygen species (mtROS) function as a major promoter in sepsis. In this proposal, we will use the heart as a model system to study the pathological responses to mtROS during sepsis and to explore therapeutic options for this disease. Based on literature and our preliminary investigations, we hypothesize that, in the heart, sepsis-induced overproduction mtROS triggers maladaptive autophagy, which plays a critical role in stimulating excessive inflammation and cardiac dysfunction. We further hypothesize that enhancing mtROS-specific defense by mitochondria-targeted antioxidants (MTAs) may provide significant therapeutic benefits for sepsis. We will test these hypotheses using both in vitro and in vivo sepsis models by combining approaches of molecular biology, biochemistry, histology, and physiology assessments. The studies involve determination of the mechanism underlying cardiac autophagy through mtROS (Aim 1), examination of whether autophagy is a maladaptive response (Aim 2), and preclinical evaluation of the therapeutic potential of MTAs in sepsis (Aim 3). We expect that these investigations will advance the understanding of sepsis pathology and the evaluation of MTAs will provide important translational implications.